This review concluded that clopidogrel plus aspirin was more effective and had a better safety profile than ticlodipine plus aspirin in patients who had undergone coronary stenting. The review has a number of methodological limitations, which mean that the conclusions cannot be relied upon.

Authors' objectives

To determine the efficacy and safety of clopidogrel plus aspirin compared with ticlodipine plus aspirin after coronary stenting.

Searching

MEDLINE was searched until December 2001 for papers written in English; some of the keywords used were noted in the paper. Manual searches of bibliographies of relevant studies, including review articles, were also conducted. There were no attempts to contact the study authors for information.

Study selection

Study designs of evaluations included in the review

There were no inclusion or exclusion criteria in relation to the study design. The studies included in the review were randomised controlled trials (RCTs) and registry-based observational studies.

Specific interventions included in the review

The intervention was treatment with clopidogrel plus aspirin. In the included studies, clopidogrel was given with or without a loading dose at a dose of 75 mg/day for two or four weeks. The control treatment was ticlodipine plus aspirin; the dose of ticlodipine used in the included studies was not given.

Participants included in the review

The participants of interest were those who had undergone coronary stenting. No details of the included participants were given, other than to state that one trial included a very low-risk population whereas some of the registry-based studies were based on higher risk populations.

Outcomes assessed in the review

There were no inclusion or exclusion criteria in relation to the outcomes, other than that the data had to be extractable for different outcomes.

The primary outcome for efficacy was a composite end point of death or nonfatal myocardial infarction (MI) at 30 days. The secondary outcome was the composite end point of major adverse cardiac events (MACE), which were included according to the definitions used in the individual studies. The individual end points of death, MI, target vessel revascularisation and subacute stent thrombosis were also analysed.

The primary outcome for safety was a composite end point of major adverse side-effects, which were included according to the definitions used in the individual studies (e.g. bone marrow suppression, drug intolerance). The secondary outcomes were the rate of major bleeding and drug intolerance.

How were decisions on the relevance of primary studies made?

The authors stated that three investigators reviewed the manuscripts and resolved any disagreements by consensus.

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

The authors referenced a publication in which the methods used for abstracting the data were described (see Other Publications of Related Interest). In that publication, they stated that two reviewers abstracted the data and a third reviewer resolved any disagreements. The data presented for each study were: the number of patients, type of study, reported outcomes and definition of MACE, length of follow-up, clopidogrel therapy regime, numbers of events, and odds ratio (OR) for the primary composite end point.

Methods of synthesis

How were the studies combined?

The results from the studies were combined into a common OR using a fixed-effect model (Mantel-Haenszel).

How were differences between studies investigated?

Differences between the studies were investigated using Q statistics to test for heterogeneity. Subgroup analyses were performed according to study design and the use (or not) of a loading dose.

Results of the review

Ten studies involving 11,688 patients were included in the review: 3 RCTs (2,736 patients) and 7 registry-based studies (8,952 patients). All 10 studies were used for efficacy analyses, while 4 to 7 studies were used for safety analyses.

Efficacy.

Composite end point of death or MI at 30 days: patients using clopidogrel plus aspirin had a lower risk of death or MI than patients on ticlodipine plus aspirin (OR 0.63, 95% CI: 0.47, 0.85, P=0.003).

There were no significant differences between groups for individual efficacy end points.

Safety.

Composite end point of major adverse side-effects: patients using clopidogrel plus aspirin had a lower risk of major adverse side-effects than patients on ticlodipine plus aspirin (OR 0.53, 95% CI: 0.42, 0.66, P<0.00001).

The authors stated that there was significant heterogeneity between the studies (P=0.07) for the primary end point analyses, but not for the individual analyses of death or MI.

When data from RCTs only were pooled, the risk of death or MI was similar in both treatment groups (OR 1.05, 95% CI: 0.52, 2.12, P=0.9).

When the results were stratified according to having a loading dose of clopidogrel or not, the treatment advantage of clopidogrel was stronger in patients treated with a loading dose than in those treated without a loading dose; the ORs for the combined end point were 0.58 (95% CI: 0.41, 0.80) and 1.16 (95% CI: 0.58, 2.32), respectively, with and without a loading dose.

Other individual results were reported in the paper.

Authors' conclusions

Clopidogrel showed superior clinical efficacy and a significantly better safety profile than ticlodipine in patients who had undergone coronary stenting.

CRD commentary

The authors set out to investigate a clear research question,but have limited their ability to answer this with certainty on account of a number of methodological limitations. The search strategy used relied on only one database (MEDLINE) and was restricted to English language papers. In addition, the search terms used do not appear to be comprehensive, although there was insufficient information to confirm this. It is possible that studies were missed, thus introducing language or publication bias into the review. The quality of the studies included in the review was not assessed, and two of the included studies were reported only as abstracts. It is therefore difficult to draw any conclusions about the reliability of the results obtained from this review.

There was no information from the primary studies about the kind of patients who were included, thus it is unclear what patients (age, gender, co-morbidities, and so on) may benefit from treatment. The authors chose to combine studies of different designs, although they also presented the results of RCTs and observational studies separately. Results from RCTs are considered to be more reliable than those from observational studies. In addition, despite reporting significant heterogeneity, the authors presented pooled results from fixed-effect models. If it was considered appropriate to pool the studies, a random-effects model would have given a more conservative estimate with wider CIs. The effectiveness of clopidogrel over ticlodipine did not reach statistical significance for any of the subgroup analyses when only RCT data were analysed. The authors overlooked this point when drawing conclusions from their data. The authors' conclusions are not fully upheld in the light of these criticisms.

Implications of the review for practice and research

Practice: The authors stated that the additional benefits of clopidogrel over ticlodipine would overcome the cost of substituting one drug for the other in several countries.

Research: The authors did not state any implications for further research.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.